Why the Tuberculosis Bacterium Sickens Some but not Others

Tuberculosis is caused by a bacterium, Mycobacterium tuberculosis, which is not very common in the United States. That’s lucky for Americans because researchers have identified a common genetic variation that increases a person’s risk of developing tuberculosis. The work, by scientists at Rockefeller University, has also found genetic mutations that disrupt the ability of the immune system to respond to other more common microbes from the same family. The findings, which were reported in Science Immunology, illustrate how people can be predisposed to tuberculosis.

Incredibly, around twenty percent of the global population is infected with Mycobacterium tuberculosis, but only about ten percent of the infected individuals show any signs of illness. In most cases, the human immune system can fight off the pathogen successfully on its own. But if there is a problem in the immune system, it causes symptoms like coughing, chest pains, fever, loss of appetite and weight loss. The infection can damage organs and in some people, can cause death.

Professor and Howard Hughes Medical Institute Investigator Jean-Laurent Casanova wanted to know why some people get sick from exposure to TB while others don’t have any issue with it. While the human genome carries the same genes in everyone, tiny changes within those genes can give rise to significant biological changes. Casanova collaborated with clinicians around the world to gather DNA from TB patients and take a closer look at some of those variants. It was found that when a person carries two copies of a variation in a gene that encodes for the TYK2 enzyme, their risk of TB is raised. It also turned out that a lot of people are carrying those variants.

"In Europeans, one in 600 people have two copies of this TYK2 variation. And in the rest of the population the rate is between one in 1,000 to one in 10,000, which is still not rare," said Casanova. "Here at Rockefeller, there are probably around four to six people who have this genetic predisposition to TB,” he added. That doesn’t mean that those people will end up with the disease. In fact, they probably won't.

People only get TB when they come into contact with the infectious pathogen, Mycobacterium tuberculosis. While the risk of that happening is very low in the US and Europe, a New York native that carries a TYK2 mutation might learn they are genetically vulnerable if they end up in a place where there are lots of those microbes.

"In New York, someone can have this mutation and their risk of getting TB is effectively zero. But if that person goes to work in a TB hospital in Africa, then the likelihood of getting TB is high--one hundredfold higher than it would be for a person without the genetic variant,” explained Casanova.

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